Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>

ABSTRACT Phylogenomic footprinting is an approach for ab initio identification of genome-wide regulatory elements in bacterial species based on sequence conservation. The statistical power of the phylogenomic approach depends on the degree of sequence conservation, the length of regulatory elements,...

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Autores principales:	Che I. Martin, Tika Y. Sukarna, Saymon Akther, Girish Ramrattan, Pedro Pagan, Lia Di, Emmanuel F. Mongodin, Claire M. Fraser, Steven E. Schutzer, Benjamin J. Luft, Sherwood R. Casjens, Wei-Gang Qiu
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
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spelling	oai:doaj.org-article:3c0992910e414960a014d8bd104cad132021-11-15T15:41:33ZPhylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>10.1128/mBio.00011-152150-7511https://doaj.org/article/3c0992910e414960a014d8bd104cad132015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00011-15https://doaj.org/toc/2150-7511ABSTRACT Phylogenomic footprinting is an approach for ab initio identification of genome-wide regulatory elements in bacterial species based on sequence conservation. The statistical power of the phylogenomic approach depends on the degree of sequence conservation, the length of regulatory elements, and the level of phylogenetic divergence among genomes. Building on an earlier model, we propose a binomial model that uses synonymous tree lengths as neutral expectations for determining the statistical significance of conserved intergenic spacer (IGS) sequences. Simulations show that the binomial model is robust to variations in the value of evolutionary parameters, including base frequencies and the transition-to-transversion ratio. We used the model to search for regulatory sequences in the Lyme disease species group (Borrelia burgdorferi sensu lato) using 23 genomes. The model indicates that the currently available set of Borrelia genomes would not yield regulatory sequences shorter than five bases, suggesting that genome sequences of additional B. burgdorferi sensu lato species are needed. Nevertheless, we show that previously known regulatory elements are indeed strongly conserved in sequence or structure across these Borrelia species. Further, we predict with sufficient confidence two new RpoS binding sites, 39 promoters, 19 transcription terminators, 28 noncoding RNAs, and four sets of coregulated genes. These putative cis- and trans-regulatory elements suggest novel, Borrelia-specific mechanisms regulating the transition between the tick and host environments, a key adaptation and virulence mechanism of B. burgdorferi. Alignments of IGS sequences are available on BorreliaBase.org, an online database of orthologous open reading frame (ORF) and IGS sequences in Borrelia. IMPORTANCE While bacterial genomes contain mostly protein-coding genes, they also house DNA sequences regulating the expression of these genes. Gene regulatory sequences tend to be conserved during evolution. By sequencing and comparing related genomes, one can therefore identify regulatory sequences in bacteria based on sequence conservation. Here, we describe a statistical framework by which one may determine how many genomes need to be sequenced and at what level of evolutionary relatedness in order to achieve a high level of statistical significance. We applied the framework to Borrelia burgdorferi, the Lyme disease agent, and identified a large number of candidate regulatory sequences, many of which are known to be involved in regulating the phase transition between the tick vector and mammalian hosts.Che I. MartinTika Y. SukarnaSaymon AktherGirish RamrattanPedro PaganLia DiEmmanuel F. MongodinClaire M. FraserSteven E. SchutzerBenjamin J. LuftSherwood R. CasjensWei-Gang QiuAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Che I. Martin Tika Y. Sukarna Saymon Akther Girish Ramrattan Pedro Pagan Lia Di Emmanuel F. Mongodin Claire M. Fraser Steven E. Schutzer Benjamin J. Luft Sherwood R. Casjens Wei-Gang Qiu Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>
description	ABSTRACT Phylogenomic footprinting is an approach for ab initio identification of genome-wide regulatory elements in bacterial species based on sequence conservation. The statistical power of the phylogenomic approach depends on the degree of sequence conservation, the length of regulatory elements, and the level of phylogenetic divergence among genomes. Building on an earlier model, we propose a binomial model that uses synonymous tree lengths as neutral expectations for determining the statistical significance of conserved intergenic spacer (IGS) sequences. Simulations show that the binomial model is robust to variations in the value of evolutionary parameters, including base frequencies and the transition-to-transversion ratio. We used the model to search for regulatory sequences in the Lyme disease species group (Borrelia burgdorferi sensu lato) using 23 genomes. The model indicates that the currently available set of Borrelia genomes would not yield regulatory sequences shorter than five bases, suggesting that genome sequences of additional B. burgdorferi sensu lato species are needed. Nevertheless, we show that previously known regulatory elements are indeed strongly conserved in sequence or structure across these Borrelia species. Further, we predict with sufficient confidence two new RpoS binding sites, 39 promoters, 19 transcription terminators, 28 noncoding RNAs, and four sets of coregulated genes. These putative cis- and trans-regulatory elements suggest novel, Borrelia-specific mechanisms regulating the transition between the tick and host environments, a key adaptation and virulence mechanism of B. burgdorferi. Alignments of IGS sequences are available on BorreliaBase.org, an online database of orthologous open reading frame (ORF) and IGS sequences in Borrelia. IMPORTANCE While bacterial genomes contain mostly protein-coding genes, they also house DNA sequences regulating the expression of these genes. Gene regulatory sequences tend to be conserved during evolution. By sequencing and comparing related genomes, one can therefore identify regulatory sequences in bacteria based on sequence conservation. Here, we describe a statistical framework by which one may determine how many genomes need to be sequenced and at what level of evolutionary relatedness in order to achieve a high level of statistical significance. We applied the framework to Borrelia burgdorferi, the Lyme disease agent, and identified a large number of candidate regulatory sequences, many of which are known to be involved in regulating the phase transition between the tick vector and mammalian hosts.
format	article
author	Che I. Martin Tika Y. Sukarna Saymon Akther Girish Ramrattan Pedro Pagan Lia Di Emmanuel F. Mongodin Claire M. Fraser Steven E. Schutzer Benjamin J. Luft Sherwood R. Casjens Wei-Gang Qiu
author_facet	Che I. Martin Tika Y. Sukarna Saymon Akther Girish Ramrattan Pedro Pagan Lia Di Emmanuel F. Mongodin Claire M. Fraser Steven E. Schutzer Benjamin J. Luft Sherwood R. Casjens Wei-Gang Qiu
author_sort	Che I. Martin
title	Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>
title_short	Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>
title_full	Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>
title_fullStr	Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>
title_full_unstemmed	Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>
title_sort	phylogenomic identification of regulatory sequences in bacteria: an analysis of statistical power and an application to <named-content content-type="genus-species">borrelia burgdorferi</named-content> <italic toggle="yes">sensu lato</italic>
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/3c0992910e414960a014d8bd104cad13
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Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to <named-content content-type="genus-species">Borrelia burgdorferi</named-content> <italic toggle="yes">Sensu Lato</italic>

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